AB0424 A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF ALPN-303, A POTENT DUAL BAFF/APRIL INHIBITOR, IN ADULT HEALTHY VOLUNTEERS
Authors: P. Harrison, J. Lickliter, S. R. Dillon, K. Manjarrez, A. Smith, M. Dossey, L. Blanchfield, A. Chunyk, H. Zayed, S. L. Peng
Journal: Annals of the Rheumatic Diseases (2022)

Background Therapeutic agents targeting the B-cell cytokines BAFF and/or APRIL, including the wild-type (WT) TACI-Fc fusion proteins atacicept and telitacicept, have demonstrated promising clinical potential in rheumatic diseases like systemic lupus erythematosus (SLE) and/or other B-cell-related diseases such as autoantibody-related nephritides. ALPN-303 is an Fc fusion protein of a variant, engineered TACI domain which mediates significantly more potent inhibitory activity in vitro as compared to WT TACI-Fc or BAFF- or APRIL-specific monoclonal antibodies, along with enhanced pharmacokinetic (PK) and immunomodulatory properties in preclinical studies 1,2 . ALPN-303 may therefore significantly improve clinical outcomes in SLE and other B-cell-related diseases. Objectives To evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of ALPN-303 in adult healthy volunteers (HV). Methods In this first-in-human study ( NCT05034484 ), adult HVs are enrolled in single ascending dose cohorts of intravenously (IV) or subcutaneously (SC) administered ALPN-303. For each IV cohort, the first 2 subjects are randomized 1:1 to receive ALPN-303 or placebo, followed by the remaining 4 subjects randomized 3:1 to receive ALPN-303 or placebo. For each SC cohort, HVs are randomized 4:2 to receive a single SC dose of ALPN-303 or placebo. All subjects are followed to assess safety and PK of ALPN-303, to measure levels of circulating immunoglobulins (Ig), and to characterize leukocyte populations in peripheral blood by flow cytometry. Results ALPN-303 has been well tolerated and overall exhibits dose-dependent PK and expected PD effects on circulating Ig levels. Dose escalation is expected to be completed by the time of the meeting; the presentation will include all available safety, PK, and PD (circulating Ig and B-cell population) data. Conclusion In this first-in-human study, ALPN-303 demonstrates acceptable preliminary safety and tolerability, and exhibits expected PD effects on circulating Ig and B-cell populations. These findings support future clinical development of ALPN-303 in patients with SLE or other B-cell-mediated diseases. References [1]Dillon SR, Evans LS, Lewis KE, et al. OP0039 ALPN-303, an enhanced, potent dual BAFF/APRIL antagonist engineered by directed evolution for the treatment of systemic lupus erythematosus (SLE) and other B cell related autoimmune diseases. Annals of the Rheumatic Diseases 2021;80:21. [2]Dillon SR, Evans LS, Lewis KE, et al. ALPN-303, an enhanced, potent dual BAFF/APRIL antagonist engineered by directed evolution for the treatment of systemic lupus erythematosus (SLE) and other B cell-related diseases. Arthritis Rheumatol. 2021; 73 (suppl 10). Disclosure of Interests Pille Harrison Employee of: Alpine Immune Sciences Inc, Jason Lickliter Consultant of: ENA Oncology and Amplia. Neither of these were developing drugs for rheumatological diseases., Stacey R. Dillon Employee of: Alpine Immune Sciences Inc, Kristi Manjarrez Employee of: Alpine Immune Sciences Inc, Alina Smith Employee of: Alpine Immune Sciences Inc, Melody Dossey Employee of: Alpine Immune Sciences Inc, Lori Blanchfield Employee of: Alpine Immune Sciences Inc, Allison Chunyk Employee of: Alpine Immune Sciences Inc, Hany Zayed Employee of: Alpine Immune Sciences Inc, Stanford L. Peng Employee of: Alpine Immune Sciences Inc